Ovary

CK7+/CK20-
Serous cystadenomas of the ovary
Serous cystadenomas of the ovary

the papillae had simple architecture with no secondary branching

serous cystadenofibroma
Serous Cystadenofibroma, Borderline

many papillary structures show hierarchical branching from larger to

progressively smaller papillae,
Serous Borderline Tumor
Serous Borderline Tumor
Serous Borderline Tumor : Micropapillary
Low-grade serous carcinoma
High grade serous

branching papillae lined by highly atypical nuclei.

Serous Tubal Intraepithelial Carcinoma
Mucinous Cystadenoma
Borderline
Mucinous carcinoma
Endometrioid Borderline Tumor
Clear Cell Adenofibroma
Clear Cell carcinoma

PAX8+ /HNF1B+ / Napsin A+

 • Clear cell carcinoma:
HNF1β +: sensitive but not specific
MSH2 mutation
Negative ER, WT1

DDX: steroid cell tumor:

Benign Brenner
Malignant brenner
MMMR
• CA-125 Elevated in Epithelial ovarian cancer.

• High garde serous carcinoma: BRACA1/BRACA2/ P53 mutaions

• Low grade serous carcinoma: K-RAS/BRAF/ ERBB2(Her-2)

• Mucinous carcinoma: K-RAS

• Endnometroid and clear cell carcinoma: associated with

Endometriosis /K-RAS- PTEN- MSI and B-Catnin muations

• Brenner tumor: Unilateral , most are begin and low grade

IHC panel :
• Serous carcinoma: PAX8+/ WT1+/ ER+/PR+
(P53 Mutant in High grade serous)

• Mucinous carcinoma: PAX8+ , if negative , R/O mets

• Clear cell carcinoma: PAX8+/ HNF1B+/NapsinA+

 Germ cell tumor
• Dysgerminoma.
• Yolk sac tumor
• Choriocarcinoma
• Teratoma
• SALL4 (nuclear) is positive in germ cell tumors.
• OCT3/4 (nuclear) positivity narrows the differential of germ
cell tumors to dysgerminomas and embryonal carcinomas.

• Dysgerminomas are positive for CD117 and D2-40.

• Glypican 3 positive in yolk sac tumor.
• CD30 (membranous) positive in embryonal carcinoma
( SOX2).
 Dysgermnioma
• Most common malignant ovarian germ cell tumor.
• Positive for SALL4, OCT3/4, D2-40, CD117, PLAP., NANOG

• In addition to dysgerminomas being the most common

neoplasm seen in pregnancy, an elevated level of hCG should
always lead one to consider pregnancy.

• Radiosensitive but respond well to chemo

• Excellent prognosis with chemotherapy.
• Unilateral tumor (90%).
• All are malignant.
• May contain granuloma.
• May contain small cystic teratoma.
• May contain syncytiotrophoblastic giant cells …elevated chorionic
gonadotrpin ( HCG).
• May occur in pt with gonadal dygenesis.
• Coexist with Gonadoblastoma.
Which of the following immunostains are typically positive in
dysgerminoma and can confirm the diagnosis?

A. AFP, SALL4, OCT3/4, hCG

B. D2-40, CD117, OCT3/4, SALL4
C. OCT3/4, EMA, hCG, SALL4
D. PLAP, AFP, hCG, AE1/3
• Gross
Strong nuclear staining for OCT4.
Membranous staining for CD117.
 Yolk sac tumor
• 2nd most common malignant germ cell tumor.
• Elaborate AFP
• Rapidly growing pelvis mass involve single ovary.

• immunohistochemical expression of SALL4 (nuclear),

glypican 3 (Cytoplasmic or membranous staining)
• and AFP

• AFP: highly specific but 60% sensitive, often patchy / focal and weak
• Glypican 3: less specific but stronger expression
• Usually unilateral ovarian mass with predilection for
right ovary.

• Respond to chemotherapy.
Gross: gelatinous cut surface
Most common pattern
Glandular pattern
Schiller-Duval body
Which immunohistochemical markers are useful for differentiating this ovarian tumor
from a dysgerminoma?

A. CD10, FOXL2, glypican 3 and SALL4

B. FOXL2, CD30, SALL4 and OCT 3/4
C. OCT 3/4, glypican 3, inhibin and SF1
D. OCT 3/4, glypican 3, CD30 and AFP
E. SALL4, CD10, glypican 3 and CD30
 Choriocarcinoma
• May develop from ovarian pregnancy (gestational choriocarcinoma), as a
germ cell tumor (pure or mixed, non-gestational choriocarcinoma) or as a
surface epithelial tumor with choriocarcinomatous differentiation.
• Primary ovarian choriocarcinomas are more common in children and
adolescents.
• After puberty, origin from an ovarian ectopic pregnancy cannot be
excluded.
• In contrast to gestational choriocarcinomas, non-gestational
choriocarcinomas are difficult to treat, generally unresponsive to
chemotherapy.
• Metastases to lungs, liver, bone and viscera are common at diagnosis.
• Aggressive
• Mets hematogenosuly to lung , liver and bone.
• Unresponsive to chemotherapy.
• Can be confirmed only in prepubrtal female, because after
this age an origin from ovarian ectopic pregnancy cannot be
excluded.
Hemorrhagic mass
• Composed of cytotrophoblast, intermediate trophopblast and
multinucleated syncytiotrophoblast around periphery of blood channels

• Cytotrophoblasts have clearly defined cytoplasmic borders, are

mononucleated with vesicular nuclei and distinct nucleolus

• Syncytiotrophoblasts contain basophilic to amphophilic cytoplasm with

mutiple nuclei
 Embryonal carcinoma
• Similar to testicular embryonal carcinoma
• Median age 15 years, patients often present with precocious
puberty, also vaginal bleeding, amenorrhea and hirsutism

• Serum hCG always high (positive pregnancy test), AFP

sometimes high
• Sheets and nests of large primitive cells, occasional papillae
and abortive glands
• Syncytiotrophoblast-like tumor cells seen (hCG+).

• Positive for SALL-4, SOX2, OCT3/4, CD30.

 Polyembryoma
• Embryonal carcinoma composed primarily of embryoid bodies.
• Elevation AFP and HCG
• Embryoid body has amniotic cavity-like structure and is continuous with
intestinal duct, and rarely has squamous cell nests, while "yolk sac" is
continuous with hepatic tissue.
• Embryoid bodies are composed of a hyperchromatic disc of embryonal
carcinoma
• Surrounding the disc of embryonal carcinoma is edematous stroma forming
a cavity lined by yolk sac epithelium

• OCT3 / 4, CD30 and keratin (embryonal carcinoma component)

• Glypican 3, AFP and keratin (yolk sac component)
 Sex cord
• Fibroma , cellular fibroma, fibrosarcoma.
• thecoma, luteinized thecoma associated with sclerosing peritonitis.

• Signet ring stromal tumor

• Sclerosing stromal tumor.
• Mircocytic stromal tumor.

• Steroid cell tumor.

• Granulosa cell tumor.

• Sex cord stromal tumor with annular tubules. (Peutz-Jeghers syndrome)
• Setroli –lyidg cell tumor (DICER)
 Fibroma:
• Most common ovarian stromal tumor (Q)
• Gorlin syndrome (PTCH) should be suspected in young patients with bilateral
ovarian fibroma
• Also associated with Meigs syndrome.

Important differential diagnoses for

cellular fibroma include diffuse adult
type granulosa cell tumor and
fibrosarcoma

Reticulin:
differentiates fibroma (individual pericellular
reticulin staining pattern) from diffuse type
of adult granulosa cell tumor (nested
reticulin staining pattern)
?????
 Granulosa cell tumor

Adult type Juvenile type

95% 5% Almost always
occurs in patients
younger than 30
years

brisk mitotic rate < 3/10HPF high mitotic rate 7-11/10HPF

Call-Exner bodies No Call-Exner bodies

>95% FOXL2 mutation positive 90% FOXL2 mutation negative

Somatic mutations in IDH1 or IDH2 are associated

with Ollier disease or Maffucci syndrome
 Adult type Juvenile type

Pale nuclei with Groove . hyperchromatic ungrooved nuclei

Scant cytoplasm Abundant eosinophilic cytoplasm.

brisk mitotic rate < 3/10HPF high mitotic rate 11/10HPF

 Granulosa cell tumor

Juvenile
Adult type type
95% 5%

Unilateral Unilateral
Yellow/ tan in color. Yellow/ tan in color.
Solid/cystic Solid/cystic
IHC panel include: IHC panel include:
•Inhibin : + •Inhibin : +
•calretinin : + •calretinin : +
•FOXL2 : + •FOXL2 : +
•SF1:+ •SF1:+
•EMA -ve •EMA +ve
Granulosa cell tumor

• reticulin special stain • reticulin special stain

Adult type Juvenile type
95% 5%
BRG1 (SMARCA4):
Retained

Various patterns, including: •Diffuse or nodular appearance at low

1. Diffuse (the most common), power.
2. Trabecular and corded.
•Macrofollicle and microfollicle formation
3. Insular
containing eosinophilic secretions
4. Microfollicular
5. Macrofollicular (the least common) Tumor cells are often
6. Gyriform pattern luteinized

Prognostic factors (worse) Usually stage IA and associated with a

Stage (most important) and tumor rupture favorable prognosis
• Granulosa cell tumor-adult:
often unilateral

• Solid yellow mass.

• Solid and cystic tumor

 Granulosa cell tumor, adult type
Luteinized adult type (such as during pregnancy):
rare (1%) if extensive (> 50%), plump cells with moderate to abundant eosinophilic
cytoplasm, conspicuous nucleoli, no nuclear grooves, myxoid or edematous stroma;
may resemble steroid cell tumor

Luteinized tumor cells with more

eosinophilic pale cytoplasm, round
nuclei and conspicuous nucleoli
Classic diffuse pattern
Trabecular pattern
Corded pattern
Insular pattern
Microfollicular pattern

Call Exner bodies are seen

Macrofollicular pattern
• Granulosa cell tumor-adult:
often unilateral
•FOXL2 immunostain is a sensitive
(80%) and specific (99%) marker for sex
Angulated, pale nuclei with cord stromal tumors (SCST)
nuclear grooves. •Inhibin A: more specific marker
•Calretinin

•EMA -
 Granulosa cell tumor, adult type
Positive stains
• FOXL2 (nuclear) immunostain is a sensitive (80%) and specific (99%) marker for sex cord
stromal tumors (SCST), superior to α inhibin and calretinin and is positive in almost all SCST
(98%) with FOXL2 mutation and a large number of those without mutation (67%);

• SF1: most sensitive marker for this as well as most common sex cord stromal tumors

• Inhibin A: more specific marker

• Calretinin

• Reticulin: shows lack of pericellular staining and highlights nests or large groups of granulosa
cells and vessels, helps differentiate diffuse pattern from fibrothecoma

• Low molecular weight cytokeratin (CAM5.2, AE1 / AE3): 30 - 60%, usually dot-like or globoid
perinuclear pattern but CK7 is negative.

• S100: 50% , CD99: 70%, Vimentin

 Granulosa cell tumor, adult type

Diffuse cytoplasmic staining with inhibin Diffuse cytoplasmic staining with calretinin
 Granulosa cell tumor, adult type

Reticulin stain shows fiber staining around large groups of tumor cells
(rather than individual cells such as in fibrothecomas)
 Granulosa cell tumor

Adult type Juvenile type

95% 5%

DDX Endometrial stromal sarcoma

Various patterns, including: Cellular fibroma or cellular thecoma

1. Diffuse Metastatic breast carcinoma (lobular)
2. Trabecular and corded Metastatic melanoma

3. Insular Carcinoid tumor

4. Microfollicular Endometrioid carcinoma , Carcinoid tumor

5. Macrofollicular Sex cord tumors with annular tubules
6. Gyriform pattern
7. extensively luteinized Steroid cell tumor
pattern
Juvenile granulosa cell tumor
Juvenile Granulosa cell tumor
Q: 3 Y/O pt with enlarged breast and ovarian mass?

Loose edematous
areas with abortive
follicles Compact spindle cell areas with
hemangiopericytoma like pattern
Juvenile Granulosa cell tumor

Solid growth
Juvenile Granulosa cell tumor

Lobulated growth pattern

 Juvenile Granulosa cell tumor
Q: pt with enlarged breast and ovarian mass?

• Diffuse or macrofollicular patterns with microcysts containing eosinophilic

secretions, tumor cells either have scant cytoplasm or are luteinized
Round / oval hyperchromatic nuclei with small nucleoli, irregular nuclear
contours
• No / rare nuclear grooves; high mitotic rate (mean 7/10 HPF)

• Has follicles with irregular size and shape, no Call-Exner bodies, brisk
mitotic activity and can have areas of higher grade atypia
• 90% FOXL2 mutation negative
• EMA+

• Adult granulosa cell tumor: more regularly shaped follicles with

basement membrane material, prominent nuclear grooves and no
hyperchromasia
– Immunohistochemical panel could include inhibin, calretinin, FOXL2(nuclear) SF1,
EMA( –ve) and reticulin special stain
 Sex cord stromal tumor with annular tubules

• a characteristic histologic appearance, which includes a dominant pattern of

simple or complex tubules, containing eosinophilic basement membrane material
(hyaline bodies). The nuclei of the tumor cells are oriented peripherally from the
hyaline center .

• Sporadic tumors tend to show more complex growth pattern. And unilateral.

• Tumor in association with Peutz-Jeghers syndrome ( PJS) are often small,

incidental, and bilateral.
• Calcification is often seen in those arising in association with PJS
This is sex cord tumor with annular tubules.
Sex cord–stromal tumor with annular
tubules
Sex cord-stromal tumor with annual
tubules
Sex cord–stromal tumor with annular tubules
• Leydig cell tumors are often testosterone producing and occur in the hilus
(hilus cell tumor) or in the stroma.

• The classic histologic features include a nested growth of eosinophilic

tumor cells with abundant granular or vacuolated cytoplasm.

• Nuclei are central and have a small prominent nucleolus.

• Reinke crystals adiagnostic finding of these tumors, are eosinophilic rod-

shaped crystalloids in the cytoplasm.

• In the absence of Reinke crystals, if the tumor shows classic histologic

findings, the diagnosis can still be made, because the crystals may only be
seen by electron microscopy.
Leydig cell tumor with Reinke crystals
 Pregnancy luteoma

Steroid tumor of pregnancy (pregnancy luteoma) is often bilateral, multifocal and

presents in pregnant patients.

Morphologically they are indistinguishable from steroid cell tumors

 Steroid Cell Tumors,
• Steroid cell tumors not otherwise specified (NOS) are those steroid cell tumors that cannot be classified as
Leydig cell tumors.

• because of lack of Reinke crystals, or because of their location.

• They produce androgens or estrogens, but other hormones such as progesterone or cortisol secretion have
been reported.

• Grossly they have similar appearance to Leydig cell tumors.

– but tend to be larger,
– may contain hemorrhage, necrosis, or cystic degeneration

Leydig cell tumors are often testosterone producing and occur in the hilus (hilus cell tumor) or in the stroma
The classic histologic features include a nested growth of eosinophilic tumor cells with abundant granular or
vacuolated cytoplasm . Nuclei are central and have a small prominent nucleolus.

Reinke crystals a diagnostic finding of these tumors, are eosinophilic rod-shaped crystalloids in the cytoplasm.
They are more likely to be found in the tumors arising in the ovarian stroma.

In the absence of Reinke crystals, if the tumor shows classic histologic findings, the diagnosis can still be made,
because the crystals may only be seen by electron microscopy.
 Steroid Cell Tumors,
• Microscopically the tumor cells show solid growth or small aggregates,
and cytologically show distinct cell borders, abundant eosinophilic
granular or lipid-rich clear and vacuolated cytoplasm

• Cytologic atypia is usually minimal and mitotic activity is low, less than
2 per 10 HPF.

• Malignant clinical behavior:

1. Extraovarian disease at the time of presentation,
2. large size (>7 cm),
3. increased mitotic index (>2 per 10 HPF),
4. necrosis, and
5. significant cytologic atypia
 Steroid Cell Tumors
abundant eosinophilic granular cytoplsm

lipid-rich clear and vacuolated cytoplasm

 They produce
androgens or estrogens,
but other hormones
such as progesterone or
cortisol secretion have
been reported.
Steroid cell tumor

Lobulated and yellow-orange

DDX steroid cell tumor:

• Clear cell carcinoma:

HNF1β +: sensitive but not specific
MSH2 mutation
Negative ER, WT1
 Smooth contoured
nests of bland
transitional epithelium
within fibromatous
stroma
• Brenner tumor usually unilateral (CK7+/CK20-) With benign
looking urothelium.
– Brenner tumors of the ovary typically GATA3 and p63 positive

• Metastatic urothelial carcinoma is bilateral but ugly looking

urothelium (CK7+/CK20+)
– History of urothelial carcinoma
– Bilateral and multinodular growth
– Lacks benign Brenner component
Brenner tumors of the ovary typically have which of the
following immunophenotypes?
A. GATA3 and ER positive
B. GATA3 and p63 positive
C. GATA3 and WT1 positive
D. GATA3 positive and mutant pattern p53 expression

Board review style answer

• B. GATA3 and p63 positive
• NOTE: Unusual presentations peculiar to mature teratoma include neuropsychiatric syndrome
secondary to autoimmune encephalitis due to antibodies against the N-methyl-D-Aspartate receptor
(anti-NMDAR), opsoclonus-myoclonus syndrome, juvenile dermatomyositis- like syndrome,
seronegative polyarthritis /tenosynovitis, and memory deficits due to anti-Ri antibodies.

• Mature teratoma, cystic structure with hair and sebaceous material; this example has a
component of mucinous borderline tumor, note mucoid areas at bottom and left of cyst .
 Adenomatoid tumors
• Adenomatoid tumors are the most common benign tumor of the fallopian
tube, and display morphology that may overlap with carcinoma.

• Immunohistochemical staining supports their mesothelial lineage, as they

are positive for WT-1, pan-keratin, D2-40, and calretinin.
 Metastatic Carcinoma

• both adenomatoid tumors and carcinomas are positive for keratins, carcinoma is
usually negative for calretinin and D2-40, and may be positive for site-specific
markers (eg, CDX-2 or GATA-3 in gastrointestinal and breast primaries,
respectively).

• Signet ring cell carcinomas also demonstrate intracytoplasmic mucin, whereas

adenomatoid tumors do not.

• D2-40 and calretinin are less helpful if the differential diagnosis includes serous
carcinoma of the ovary.
 Lymphangiomas

• Lymphangiomas may occur in the fallopian tube.

• They show cystically dilated lymphatic spaces that resemble the cystic spaces of an
adenomatoid tumor.

• However, the cystic spaces contain lymphocytes, and they are negative for
calretinin.

• D2-40 may be positive in both lymphangiomas and adenomatoid tumors.

uterus
Endometrial stromal neoplasms CD10+
DDX:
• PEComa:
– Typically circumscribed and consisting of epithelioid and spindled cells
– Positive for HMB45 and smooth muscle markers, negative for CD10.
Endometrial stromal neoplasms

Low grade endometrial stromal sarcoma

• Histologic features include permeative tongue-like islands of tumor cells composed of

monotonous oval to spindle cells with minimal cytologic atypia, often demonstrating whorling
around blood vessels; smooth muscle and sex cord-like differentiation are common.

• Diagnosis may require extensive sampling of the tumor myometrial interface to evaluate for
invasion and exclude endometrial stromal nodule.

• Recurrent rearrangements involving JAZF1 and PHF1 are common, though absence does not
preclude the diagnosis
 High grade endometrial stromal
sarcoma

•Cellular tumor with high grade round

or spindle cells, sometimes with an
associated low grade component

•Variable positivity for BCOR, cyclin D1

and CD10, depending on molecular
alteration present

•Major subtypes include sarcomas

with YWHAE-NUTM2A/B fusions

•A subclassification of high grade

endometrial stromal sarcoma as per
WHO 2020 is based on Identification of
specific gene rearrangement
involving YWHAE or BCOR or internal
tandem duplication of BCOR gene
High grade
serous
carcinoma
ETT:
Composed of chorionic type
intermediate trophoblast.

characterized by a single
population of mononuclear
cells with eosinophilic to
clear cytoplasm

Diffusely positive for p63

 Mild elevated
(>1000)

ETT:
Composed of chorionic type
intermediate trophoblast.

characterized by a single
population of mononuclear
cells with eosinophilic to
clear cytoplasm

Diffusely positive for p63

ETT
ETT
 Low HCG (<1000)

Placental site trophoblastic tumor:

Composed of implantation type

intermediate trophoblast,

characterized by a single population of

mononuclear cells with eosinophilic
and amphophilic cytoplasm

Diffusely positive for hPL and Mel-CAM

characteristically infiltrating the

myometrium by separating individual
muscle fibers and groups of fibers
Placenta trophoblastic tumor
VS choriocarcinoma
Becz it lost on deeper levels , so to be save we call them atypical
This most likey PSTT
 Exaggerated placental site
Definition / general
• Exuberant infiltration of the endometrium and myometrium by implantation
site intermediate trophoblast

Essential features
• Exaggeration of normal physiologic process, with infiltration of the
endometrium and superficial third of myometrium by implantation site
intermediate trophoblast
• Can be associated with normal pregnancy or abortions, molar pregnancy
and sometimes presents as postpartum bleeding
• Ki67 labeling index is near 0%
• Ki67 labeling index can be 0 - 5 % in exaggerated placental site (EPS) of
molar pregnancie
• Chorionic villi are morphologically unremarkable
• Despite diffuse infiltration, there is not necrosis or mitoses.
 Necrotic uterine content
without villi or fetus indicates
choroicarcinoma
Intraplacental choriocarcinoma
 Inflammatory myofibroblastic tumor
Rare mesenchymal neoplasm of myofibroblastic / fibroblastic origin with variable
amounts of myxoid stroma and lymphoplasmacytic inflammatio
Essential features
• Best classified as a neoplasm of uncertain malignant potential, as histologically
bland uterine confined tumors may recur

• Comprised predominantly of spindle cells with hypercellular (fascicular /

storiform) and hypocellular (myxoid rich) areas admixed with a variably prominent
lymphoplasmacytic infiltrate

• Most express ALK, CD10, smooth muscle actin and desmin but with variable
staining intensity and distribution

• Multiple fusion partners have been identified, some with complex genetic
rearrangements, which might result in false negative FISH testing